- Left Atrial Appendage: An Underrecognized Trigger Site of Atrial Fibrillation
- Relation of Platelet and Leukocyte Inflammatory Transcripts to Body Mass Index in the Framingham Heart Study
- Heart Rate Response to Exercise Stress Testing in Asymptomatic Women: The St. James Women Take Heart Project
- Equilibrium Contrast Cardiovascular Magnetic Resonance for the Measurement of Diffuse Myocardial Fibrosis: Preliminary Validation in Humans
- Continuous Glycoprotein-130–Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction
- Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era
- Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)
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Left Atrial Appendage: An Underrecognized Trigger Site of Atrial Fibrillation
Several studies have shown that together with the pulmonary veins, many extrapulmonary vein areas may be the source of initiation and maintenance of atrial fibrillation. The most common sites are the superior vena cava, ligament of Marshall, coronary sinus, crista terminalis, and left atrial posterior wall. This study is the first to report firing from the left atrial appendage as a possible site of origin of atrial fibrillation in a consecutive series of patients. The prevalence of this finding in our population was 27%, and in 8.7% of patients, the left atrial appendage was the only target of ablation during redo procedures. We performed electric isolation of the left atrial appendage. Similar to what was observed for the isolation of the pulmonary veins, isolation of the left atrial appendage with segmental or circumferential lesions led to a higher probability of achieving long-term freedom from atrial fibrillation/atrial tachyarrhythmia than focal ablation. The clinical relevance of left atrial appendage isolation and its consequences with respect to potential complications require further investigation. See p 109.
Relation of Platelet and Leukocyte Inflammatory Transcripts to Body Mass Index in the Framingham Heart Study
There have been many genetic epidemiology and biomarker studies examining associations of common genetic variants (DNA) and circulating proteins with clinically apparent cardiovascular disease and associated risk factors; however, there has been relatively little study of gene expression or transcriptomics. Quantitative differences in the abundance of transcripts (messenger RNA) has been demonstrated in specific malignancies, but gene expression from a large community-based cohort examining cardiovascular disease or its risk factors has never been reported. In this study, we measured quantitative expression of 48 genes in 1846 participants of the Framingham Offspring cohort from RNA derived from isolated platelets and leukocytes. Specific inflammatory platelet-derived transcripts were significantly associated with higher body mass index. Compared with platelets, fewer leukocyte-derived transcripts were associated with body mass index or other cardiovascular risk factors. Select transcripts were found to be highly heritable. This study demonstrates that inflammatory transcripts derived from platelets, particularly those part inflammatory regulating pathways, are associated with BMI, whereas other distinct transcripts, many known to be related to platelet function, are heritable. This is the first study, using a large community-based cohort, to demonstrate that quantitative gene expression is associated with risk factors, most notably body mass index. See p 119.
Heart Rate Response to Exercise Stress Testing in Asymptomatic Women: The St. James Women Take Heart Project
The definition of a normal heart rate (HR) response to exercise stress testing in women is poorly understood, given that most studies describing a normative response predominately studied men. Peak HR estimates are based on the equation of 220–age, which is considered the traditional estimate and is used for both sexes. The validity of this peak HR equation in women has not been described. We examined the peak HR and chronotropic response to exercise stress testing in 5437 asymptomatic women and found that the equation:
better estimated peak HR to maximal stress testing in women, compared with the traditional estimate. In addition, incorporating this estimate for peak HR for women improved the measures of chronotropic incompetence (including inability to achieve 85% of age-predicted heart rate and a chronotropic index of <0.8) as markers of risk of all-cause mortality in women, compared with the use of the traditional estimates. Sex-specific parameters of physiological HR response to exercise should be incorporated into clinical practice. Use of this female-specific equation will improve risk prediction in women; specifically, relatively more women will achieve their age-predicted targets for greater accuracy for diagnosis and prognosis. See p 130.
Equilibrium Contrast Cardiovascular Magnetic Resonance for the Measurement of Diffuse Myocardial Fibrosis: Preliminary Validation in Humans
Diffuse myocardial fibrosis is a final common end point in cardiovascular disease and is associated with symptoms, impaired ventricular function, and adverse prognosis. Even though it is thought to be a key “missing parameter” in clinical cardiology, and it is a target for many therapies (eg, angiotensin-converting enzyme inhibitors, aldosterone antagonists), it can only be quantified by histology on biopsy, with inherent risk and sampling error. As a result, it is not well understood in the clinical arena. Echocardiographic surrogates such as markers of diastolic dysfunction are unsatisfactory because they are influenced by multiple other factors. We developed and performed initial validation for a new technique, equilibrium contrast cardiovascular magnetic resonance (EQ–CMR), as a method to quantify diffuse myocardial fibrosis. We designed it to be easy to implement on any scanner. EQ–CMR involves standard MRI technology and contrast agent and can be integrated into a standard CMR protocol. We have shown that EQ–CMR correlates with histological fibrosis in 2 conditions, aortic stenosis and hypertrophic cardiomyopathy. This work is at an early stage, but it appears that, for the first time, it is possible to measure the diffuse myocardial fibrosis burden noninvasively. With further work, this technique could have widespread implications in disease characterization, monitoring, outcome prediction, and therapeutics. See p 138.
Continuous Glycoprotein-130–Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction
High serum interleukin-6 (IL-6) levels in patients with myocardial infarction or heart failure are consistently associated with reduced cardiac function and a poor outcome (ie, increased morbidity and mortality). This observation contrasts with experimental data that suggest cardioprotective effects mediated by the common receptor subunit glycoprotein-130 (gp130), of IL-6 cytokines. IL-6 cytokine–mediated gp130 signaling involves a complex network of activating and terminating mechanisms controlling 3 major downstream signaling pathways: janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt. The degree and duration of downstream signaling activation depend at least in part on a single tyrosine residue, Y-757, at the gp130 receptor. In cardiomyocyte-specific gp130Y757F mutant mice (Y757F), the Y-757–dependent control is ablated by a point mutation leading to prolonged and enhanced JAK/STAT activation, whereas ERK and Akt signaling is absent. In response to myocardial infarction, Y757F mice displayed higher mortality associated with an increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects result from prolonged and enhanced STAT3 activation, increased expression of IL-6, and upregulated mannose-binding-lectin-C–mediated complement activation. Pharmacological inhibition of the complement system by cobra venom factor or genetic reduction of STAT3 prevented sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. This study unravels the potential adverse effects of high IL-6 cytokine levels after myocardial infarction in settings with impaired gp130 downstream signaling. In this regard, sustained IL-6–dependent and gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure. See p 145.
Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era
The management of pulmonary arterial hypertension has advanced significantly since the publication of the National Institutes of Health–supported 1980s registry, which established a prognostic benchmark for survival that is still used today. The present article reports results from the French Network on Pulmonary Hypertension national prospective registry, which investigated contemporary, “real-world” survival during a 3-year follow-up of consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension. Patients were enrolled between October 2002 and October 2003 and received treatment according to recommendations and availability. Kaplan-Meier survival estimates at 1, 2, and 3 years were 85.7%, 69.6%, and 54.9%, respectively, in incident cases, and 82.9%, 67.1%, and 58.2%, respectively, in a combined incident and prevalent population. With the use of the modeling approach of the original National Institutes of Health registry, observed survival in the current management era was improved by ≈10% versus estimates. Mortality was most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation. In summary, although survival among patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension has improved compared with historical estimates, it is clear that pulmonary arterial hypertension remains a progressive, fatal disease. Continued efforts are required to improve the management of patients with pulmonary arterial hypertension. See p 156.
Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)
The Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was designed to assess longitudinal clinical course and disease management in the largest cohort of patients with pulmonary arterial hypertension ever monitored. Pulmonary arterial hypertension remains a morbid disease unless well-timed clinical intervention is implemented. Therefore, factors that determine survival in pulmonary arterial hypertension can significantly drive and focus clinical management. We analyzed data from 2716 patients with pulmonary arterial hypertension to derive a multivariable, weighted risk formula that could be used by the practicing clinician at any time in the course of a patient’s disease progression to predict survival. Nineteen independent factors were identified as having an impact on patient survival. A multivariable risk formula comprising all 19 factors provided a more accurate assessment of clinical outcome than each independent variable. These results emphasize the importance of using the full spectrum of clinical data commonly available to the practicing clinician for the assessment of patients with pulmonary arterial hypertension. We believe that the risk stratification provided by this predictive equation will facilitate counseling of patients about their disease and prognosis and will provide a benchmark for prospective evaluation of new therapies. See p 164.
- Left Atrial Appendage: An Underrecognized Trigger Site of Atrial Fibrillation
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